Chromatin organization is a major influence on regional mutation rates in human cancer cells

@article{SchusterBckler2012ChromatinOI,
  title={Chromatin organization is a major influence on regional mutation rates in human cancer cells},
  author={Benjamin Schuster-B{\"o}ckler and Ben Lehner},
  journal={Nature},
  year={2012},
  volume={488},
  pages={504-507}
}
Cancer genome sequencing provides the first direct information on how mutation rates vary across the human genome in somatic cells. Testing diverse genetic and epigenetic features, here we show that mutation rates in cancer genomes are strikingly related to chromatin organization. Indeed, at the megabase scale, a single feature—levels of the heterochromatin-associated histone modification H3K9me3—can account for more than 40% of mutation-rate variation, and a combination of features can account… 
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543 Citations

The effects of chromatin organization on variation in mutation rates in the genome
TLDR
Recent studies showing associations between chromatin state and mutation rates, including pairwise and multivariate investigations of germline and somatic mutations, indicate an intricate interplay between the nucleotide sequence of DNA and its dynamic packaging into chromatin, and have important implications for current biomedical research.
Cancer genomics: Chromatin influence on cancer mutation rate
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The authors suggest that variability in the mutation rate in human cancer cells could reflect differences in access to DNA repair complexes, increased exposure to mutagens at the nuclear periphery or variation in the ability to signal repair.
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Scales and mechanisms of somatic mutation rate variation across the human genome.
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The default mutation rate in mammalian genomes results in active genes having low mutation rates because of a combination of factors that increase DNA repair, but either an increase in the global mutation rate or a redistribution of mutations from inactive to active DNA can increase the rate at which consequential mutations are acquired inactive genes.
Characterizing the genome-wide associations of somatic mutations and chromatin accessibility in cancer
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Interestingly, melanoma mutations were better predicted by normal melanocyte chromatin accessibility, suggesting earlier mutational timing, and chromatin state was an accurate predictor of carcinogen-induced mutation rates while the mutations of endogenous mutational processes were only weakly statistically associated.
Chromatin marks govern mutation landscape of cancer at early stage of progression
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The data suggest that the major time point for the mutation landscape establishment dictated by chromatin features is early in the process of cancer progression, and epigenetic changes due to environmental conditions at early stages can dramatically impact the somatic mutation landscape of cancer.
Differential DNA mismatch repair underlies mutation rate variation across the human genome
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It is shown that regional autosomal mutation rates at megabase resolution are largely stable across cancer types, with differences related to changes in replication timing and gene expression.
Reduced local mutation density in regulatory DNA of cancer genomes is linked to DNA repair
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It is shown that the reduced local mutation density within regulatory DNA is linked to intact global genome repair machinery, with nearly complete abrogation of the hypomutation phenomenon in individual cancers that possess mutations in components of the nucleotide excision repair system.
Genome Organization in Cancer Cells
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Understanding the interplay between genome organization and transcription in normal cell types and its perturbations in cancer will provide important insights into the causes of tumorigenesis.
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References

SHOWING 1-10 OF 34 REFERENCES
The large‐scale distribution of somatic mutations in cancer genomes
TLDR
The density of mutations is correlated to that in the germline, as measured by the divergence between humans and chimpanzees and humans and macaques, and it is found that genes associated with cancer occupy regions of the genome with significantly lower mutation rates than the average.
Chromatin structure and evolution in the human genome
TLDR
It is concluded that, overall, non-CpG mutation rates are lowest in open regions of the genome and that regions ofThe genome with a closed chromatin structure have the highest background mutation rate.
Mutation rate variation in the mammalian genome.
A comprehensive catalogue of somatic mutations from a human cancer genome
TLDR
The genomes of a malignant melanoma and a lymphoblastoid cell line from the same person are sequenced, providing the first comprehensive catalogue of somatic mutations from an individual cancer.
Mutation rates differ among regions of the mammalian genome
TLDR
It is proposed that the differences arising because mutation patterns vary with the timing of replication of different chromosomal regions in the germline can account for both the origin of isochores in mammalian genomes and the observation that silent nucleotide substitutions in different mammalian genes do not have the same molecular clock.
Sequencing newly replicated DNA reveals widespread plasticity in human replication timing
TLDR
A genome-scale approach to map temporally ordered replicating DNA using massively parallel sequencing and applied to study regional variation in human DNA replication time across multiple human cell types revealed that DNA replication typically initiates within foci of accessible chromatin comprising clustered DNaseI hypersensitive sites, and that replication time is better correlated with chromatin accessibility than with gene expression.
Combinatorial patterns of histone acetylations and methylations in the human genome
TLDR
The data suggest that a large number of histone modifications may act cooperatively to prepare chromatin for transcriptional activation and be associated with promoters and enhancers.
High-Resolution Profiling of Histone Methylations in the Human Genome
Human SNP variability and mutation rate are higher in regions of high recombination.
DNA sequencing of a cytogenetically normal acute myeloid leukemia genome
TLDR
This study establishes whole-genome sequencing as an unbiased method for discovering cancer-initiating mutations in previously unidentified genes that may respond to targeted therapies.
...
...